Tau is the main component of neurofibrillary tangles observed in Alzheimer's disease and other related neurodegenerative tauopathies, and aging is the greatest known risk factor for Alzheimer's disease. We propose here a novel mechanism by which tau and aging may interact. The objective of the current proposal, in the context of a R15 grant mechanism, is to investigate the role of extrasynaptic NMDA receptors (NMDARs) in tau- and age- related memory deficits. Activation of extrasynaptic NMDARs is associated with neurotoxicity by stimulating cell death pathways, and blockade of these receptors reduces tau hyperphosphorylation, an early pathological signature of Alzheimer's disease. The central hypothesis of this application is that tau hyperphosphorylation increases the number of extrasynaptic NMDARs that then further increase tau phosphorylation, leading to a vicious, positive feedforward loop. We hypothesize that an aged brain is more vulnerable to this cycle due to an age-related increase in the activity and number of extrasynaptic NMDARs. Specific aims of this study are to: 1. determine how an aged brain exacerbates tau pathology and memory deficits, 2. identify the in vivo consequences of aging and tau on the number of extrasynaptic NMDARs, and 3. test the hypothesis that decreasing extrasynaptic NMDAR activity will rescue memory deficits in a tau mouse model of Alzheimer's disease by decreasing tau pathology. The innovative aspects of this proposal lie in the use of (1) regulatable mouse models in which tau expression can be suppressed until mice have aged, allowing us to study the effects of aging independently of prolonged tau expression, and (2) an incredibly sensitive, longitudinal memory test with a large dynamic range, allowing us to detect subtle differences between young and aged mice. An equally important feature of the project is the training opportunities that it provides for undergraduate and graduate researchers, who will plan studies, work with laboratory animals, collect and analyze data, and present their work to the scientific community (with trips funded by WVU). The project spans many areas, including psychology, biochemistry, and neuroscience, and should, therefore, attract an array of students. The diversity of the project should also promote collaborations between students and faculty from different departments and the IDeA-funded core facilities on campus. Receipt of an AREA award will have a profound effect on the newly established Behavioral Neuroscience program in the Psychology Department at West Virginia University, by increasing the quality and quantity of opportunities for student research in biomedical science. As a young and early career investigator, an award would also support the PI's efforts to establish an independent, productive research program and will establish a foundation for further participation in NIH programs in the future.